1. Field of the Invention
This invention relates to a stabilized liposome composition capable of conveying active agents in cosmetic or pharmaceutical compositions and delivering them to the skin or other biological target such as the nails, hair, mucous membranes or even internally. The liposomes are carriers for the actives and are sometimes described as vectors for their ability to transport the active agent. More particularly, in preferred embodiments, the invention provides stabilized liposome compositions which can encapsulate or other wise contain acidic, water-soluble active ingredients, for example AHA's in cosmetic compositions, especially emulsions, such as creams lotions and gels, adequately through formulation and storage to deliver the actives to consumers, patients, or others, with their activity retained.
Liposomes or "lipid bodies", sometimes called "vesicles" are structures formed spontaneously by polar lipid molecules, or amphiphilic molecules, each having a polar head and a long hydrophobic tail, e.g. phospholipids such as lecithin. Structurally, liposomes comprise an outer shell of one or more membrane-like, bilayers of the molecules arranged concentrically around a hollow interior, or "vacuole" which can serve as a storage compartment for active agents. In the outer layer the polar heads of the molecules are oriented outwardly of the liposome, while the hydrophobic tail, e.g. palmitic or stearic acid, depends inwardly. If there are multiple layers, the orientation is reversed in alternate layers so that the lipid tails of one layer intermingle with the lipid tails of the next, and the polar heads of one layer abut those of a neighbor.
Active agents may be stored in the interior of the liposome, where they are sheltered from alien media by the surrounding membrane of amphiphilic molecules. Such active agents may or may not be dissolved in aqueous media, and are typically hydrophilic. Typically also, the liposomes are dispersed in an aqueous medium, or polar solvent medium. Lipophilic active agents can also be carried by liposomes, locating themselves in the lipid layers formed by the hydrophobic tails of the amphiphilic structural liposome material. Gas filled liposomes are also known, see for example, Unger et al. U.S. Pat. Nos. 5,580,575, 5,469,854 which disclose the use of gas-filled liposomes for medical diagnostic purposes.
Liposomes are typically quite small, under 1 micron, and small enough to transport encapsulated actives through the dermis for sub-dermal delivery. For these and other reasons, liposomes are widely used in both the cosmetics and pharmacy industries in various applications for the delivery of cosmetically and pharmacologically active substances.
However, there are significant problems to be overcome in using liposomes for cosmetic or pharmaceutical formulations intended for consumer use. Known compositions lack sufficient stability to withstand formulating conditions and have a poor shelf life. Liposome vesicles tend to fuse together, or agglomerate, particularly when they are exposed to surfactants, solvents, adverse pH conditions, or even water, for long periods of time. This instability is usually aggravated by elevated temperatures or low pH levels, under which conditions the liposome vesicles may fuse together and aggregate into quasi-gellified suspensions of the component polar lipids.
Accordingly, there have been many proposals for stabilizing liposomes. Known stabilizers for liposomes include certain relatively simple amphoteric molecules having a cationic region, for example triethanolamine, a common cosmetic buffer, can be added to phospholipid starting materials during liposome preparation to prevent aggregation. Though providing some stability, triethanolamine and the like, do not provide adequate shelf-life and processing stability to enable liposomes to protect actives in a wide range of cosmetic and pharmaceutical formulations.
2. Description of Related Art Including Information Disclosed under 37 CFR 1.97 and 37 CFR 1.98
Huc et al. ("Huc") U.S. Pat. No. 5,244,672 discloses stabilization of liposomes with a support comprising non-crosslinked, "atelo" collagen and glycosaminoglycans. This support system is reported to provides a modest reduction of permeability of the liposome membrane to a fluorescent marker, designated "6-CF". No significant shelf life or temperature stability improvements are reported.
Edgar et al. U.S. Pat. No. 5,498,420 discloses liposome preparations comprising a mixture of lecithin and a fatty acid-esterified collagen hydrolysate, "namely a fatty acid ester of a lipoaminoacid or lipopeptide", see the Abstract. The liposomes produced reportedly show room temperature stability, column 21, and are incorporated into gels. However there is no data as to stability of the produced liposomes to elevated temperatures, surfactants, solvents other than water, or acidity.
Unger et al. ("Unger") U.S. Pat. No. 5,469,854 and 5,580,575 disclose gas-filled liposomes prepared by shaking at a temperature below the gel-to-crystalline phase transition temperature, using a process wherein the ingredients are frozen in liquid nitrogen. Unger's liposomes are intended, inter alia, as vehicles for lipophilic actives, and Unger teaches a range of possible stabilizers or viscosity modifiers, emulsifiers and solubilizers, see '575 col. 9, lines 11-39. Various possible coatings are also suggested, see col. 15, lines 2-10. Unger's liposomes are relatively large, with sizes in excess of 5 micron and typically in excess of 8 micron, see '854 col. 27. A principle application is for ultrasound diagnostics and delivery of actives to target sites for ultrasound-initiated release of actives.
Unger's catalogic lists provide no guidance as to the selection of a stabilizer for the purposes described herein. Nor does Unger appear to provide any teaching regarding liposome compositions suitable for protecting active agents in cosmetic and pharmaceutical compositions, during formulation and storage. There is accordingly a need for stabilized liposomes with such useful properties.